ABSTRACT For millions of people living with HIV (PLHIV) receiving antiretroviral therapy (ART), adequate ART adherence and routine HIV viral load (VL) monitoring are critical to ensure viral suppression and good health outcomes. Initiation and management of life-long ART in low- and middle-income countries (LMICs) is challenging for both PLHIV and providers in part due to the reliance on self-reported adherence and delays with lab-based VL testing, which are part of the usual care. Drs. Drain and Garrett (co-principal investigators) recently completed a pilot study in South Africa demonstrating that point-of-care (POC) VL monitoring for PLHIV receiving efavirenz-based ART increased VL suppression and retention in care by 14% (95% CI 6-21%) over a 12-month period compared to standard lab testing. However, the applicability of these findings to the context of newer, more robust dolutegravir-based ART regimens being introduced in several LMICs, including South Africa, is not known. To complement POC VL monitoring, we have recently completed the development and initial evaluation of a novel POC urine tenofovir assay, in collaboration with Abbott Diagnostics, which can monitor ART adherence in clinic- based settings in real-time. Building on our pilot study results, our objective in this application is to determine the clinical efficacy and cost effectiveness of implementing an integrated HIV care model using POC tenofovir adherence testing and POC VL monitoring in maintaining durable VL suppression among PLHIV receiving tenofovir-based ART in South Africa. Our central hypotheses are that POC tenofovir adherence testing and POC VL monitoring will improve VL suppression rates and retention in care, while being a feasible, acceptable, and cost-effective strategy for ART management. We will objectively test our central hypotheses with three specific aims: (1) to determine if an integrated model for HIV monitoring using a POC tenofovir adherence assay and a POC VL test will improve VL suppression and retention in care; (2) to monitor implementation and assess patient and provider perspectives of real-time POC tenofovir adherence testing and POC VL monitoring in South Africa; and (3) to estimate the costs and cost-effectiveness of implementing POC tenofovir adherence testing with POC VL monitoring, compared to no objective adherence testing and lab-based VL monitoring. To complete these aims, we will randomize 534 participants (1:1) at ART initiation into regular POC tenofovir adherence testing with POC VL monitoring (Arm 1) or standard-of-care with no objective tenofovir adherence testing and lab-based VL monitoring (Arm 2). Participants will be followed to compare a primary composite outcome of VL suppression and retention in care between the study arms at 18 months after ART initiation. This randomized controlled implementation trial will provide crucial data on the clinical efficacy, acceptability, and cost-effectiveness of an integrated model of POC adherence and VL testing to inform global policy on improving HIV care in LMICs.